Technology for imaging the heart has advanced dramatically in recent years. In particular, real-time three-dimensional ultrasound (RT3D) has captured the imagination of cardiologists with its ability to obtain complete three-dimensional images of the heart over an entire cardiac cycle in just a few seconds of imaging. The wealth of information contained in such fully four-dimensional (3D plus time) cardiac images could greatly enhance clinical diagnosis, but so far it remains largely inaccessible to clinicians. The goal of this proposal is to provide a set of practical methods for extracting information from these large datasets, reducing it to quantitative, diagnostically useful measures, and presenting this information in a simple, straightforward way, all within a time frame consistent with the time demands of clinical practice. Achievement of this goal will unleash for the first time the true diagnostic power of 4D cardiac imaging. In particular, this proposal will focus on a common problem for which 4D cardiac imaging is ideally suited: screening for regions of acute ischemia (insufficient blood flow) that indicate the presence of coronary artery disease. The specific aims of this proposal are: (1) to test the hypothesis that reduced three-dimensional fractional shortening (3DFS) predicts the size and location of experimentally induced acutely ischemic regions with better accuracy than the current state of the art, segment scoring by expert cardiologists; (2) to test the hypothesis that reduced three-dimensional fractional shortening (3DFS) during dobutamine stress detects and localizes regions of angiographically confirmed coronary artery disease with better accuracy than analysis by expert cardiologists; (3) to test the hypothesis that optical flow tracking from a single manually digitized frame provides endocardial surface data for the full cardiac cycle with similar accuracy to fully manual digitizing; and (4) to use a model-based process to develop new customized 4D wall motion measures to improve quantification of the size, location, and severity of acutely ischemic regions. The significance of the proposed work is that it will provide the most accurate, least labor-intensive measures of ventricular wall motion developed to date, finally allowing clinicians to routinely measure wall motion, rather than simply assessing it qualitatively.